RARE DISEASE
Aspartylglucosaminuria
Aspartylglucosaminuria
Aspartylglucosaminuria
Synonyms: Aspartylglucosaminidase deficiency
Synonyms: Aspartylglucosaminidase deficiency
Synonyms: Aspartylglucosaminidase deficiency
Drug discovery
3
drugs
With orphan designations
Overview
Aspartylglucosaminuria (AGU) is a rare autosomal recessive lysosomal storage disorder caused by mutations in the AGA gene, leading to deficient aspartylglucosaminidase enzyme activity. This results in glycoasparagine accumulation, primarily affecting neurodevelopment. Clinical features include progressive intellectual disability, motor decline, characteristic coarse facies, joint hypermobility, and recurrent infections. Onset occurs in early childhood with symptom progression, including cognitive regression and severe physical disability by adulthood [1][6][8].
Burden
Progressive neurodegeneration leads to total dependence by adulthood, with life expectancy ≤50 years [1][6].
Multisystem involvement (skeletal, dermatologic, neurological) necessitates lifelong multidisciplinary care [8][15].
High psychosocial burden on families due to cognitive/behavioral decline and limited disease-modifying therapies [1][6][15].
Therapies
Supportive care: Seizure management, infection prophylaxis, and physical rehabilitation [6][8].
Experimental approaches: Hematopoietic stem cell transplantation (limited efficacy if delayed), pharmacological chaperones (e.g., trimethylglycine) in clinical trials, and AAV9-based gene therapy showing preclinical promise [1][3][12].
Categories: rare bone diseases, rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
39 drug discovery papers about Aspartylglucosaminuria, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
39 drug discovery papers about Aspartylglucosaminuria, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-01-07 | Pharmacological chaperone treatment with Cystadane for aspartylglucosaminuria: an open-label, phase 1b/2, clinical trial
Aspartylglucosaminuria (AGU) is a lysosomal storage disorder caused by a deficiency of the enzyme aspartylglucosaminidase (AGA) that is involved in glycoprotein breakdown. In the absence of this enzyme, glycoasparagines accumulate in the tissues and body fluids of the patients. No treatments targeting the disease cause are currently available. Our earlier findings show that betaine (tri-methyl glycine) functions as a pharmacological chaperone for the mutated AGA enzyme, resulting in an increased AGA activity in patient cells with pathogenic AGA missense variants. Here, we have carried out a phase 1b/2, open label clinical study (EudraCT number 2017-000645-48) with a clinically approved betaine product, Cystadane, in 21 Finnish AGU patients aged between 7.5 and 15 years at study begin, and homozygous for a specific missense variant. Cystadane was orally administrated for 48 months using a dose escalation strategy with a 3-month treatment break after the first year. The results of our study show that betaine is safe and well tolerated in AGU, and use of betaine results in a significant reduction of glycoasparagines in the urine, the primary endpoint of the study, as well as in a concomitant increase in serum AGA activity (a secondary endpoint). Exploratory neuropsychological findings showed significant improvements in some domains of the Wechsler’s Intelligence Scale for Children IV. Magnetic resonance imaging demonstrated that iron accumulation in specific thalamic regions of the patients is reduced due to betaine treatment. Our positive results encourage larger clinical trials with betaine in AGU.
2022-01-13 | Towards Splicing Therapy for Lysosomal Storage Disorders: Methylxanthines and Luteolin Ameliorate Splicing Defects in Aspartylglucosaminuria and Classic Late Infantile Neuronal Ceroid Lipofuscinosis.
Splicing defects caused by mutations in the consensus sequences at the borders of introns and exons are common in human diseases. Such defects frequently result in a complete loss of function of the protein in question. Therapy approaches based on antisense oligonucleotides for specific gene mutations have been developed in the past, but they are very expensive and require invasive, life-long administration. Thus, modulation of splicing by means of small molecules is of great interest for the therapy of genetic diseases resulting from splice-site mutations. Using minigene approaches and patient cells, we here show that methylxanthine derivatives and the food-derived flavonoid luteolin are able to enhance the correct splicing of the AGA mRNA with a splice-site mutation c.128-2A>G in aspartylglucosaminuria, and result in increased AGA enzyme activity in patient cells. Furthermore, we also show that one of the most common disease causing TPP1 gene variants in classic late infantile neuronal ceroid lipofuscinosis may also be amenable to splicing modulation using similar substances. Therefore, our data suggest that splice-modulation with small molecules may be a valid therapy option for lysosomal storage disorders.
2019-04-09 | The T99K variant of glycosylasparaginase shows a new structural mechanism of the genetic disease aspartylglucosaminuria
Aspartylglucosaminuria (AGU) is an inherited disease caused by mutations in a lysosomal amidase called aspartylglucosaminidase (AGA) or glycosylasparaginase (GA). This disorder results in an accumulation of glycoasparagines in the lysosomes of virtually all cell types, with severe clinical symptoms affecting the central nervous system, skeletal abnormalities, and connective tissue lesions. GA is synthesized as a single-chain precursor that requires an intramolecular autoprocessing to form a mature amidase. Previously, we showed that a Canadian AGU mutation disrupts this obligatory intramolecular autoprocessing with the enzyme trapped as an inactive precursor. Here, we report biochemical and structural characterization of a model enzyme corresponding to a new American AGU allele, the T99K variant. Unlike other variants with known 3D structures, this T99K model enzyme still has autoprocessing capacity to generate a mature form. However, its amidase activity to digest glycoasparagines remains low, consistent with its association with AGU. We have determined a 1.5-Å-resolution structure of this new AGU model enzyme and built an enzyme-substrate complex to provide a structural basis to analyze the negative effects of the T99K point mutation on KM and kcat of the amidase. It appears that a "molecular clamp" capable of fixing local disorders at the dimer interface might be able to rescue the deficiency of this new AGU variant.
2018-03-01 | Amlexanox provides a potential therapy for nonsense mutations in the lysosomal storage disorder Aspartylglucosaminuria
Aspartylglucosaminuria (AGU) is a lysosomal storage disorder caused by mutations in the gene for aspartylglucosaminidase (AGA). This enzyme participates in glycoprotein degradation in lysosomes. AGU results in progressive mental retardation, and no curative therapy is currently available. We have here characterized the consequences of AGA gene mutations in a compound heterozygous patient who exhibits a missense mutation producing a Ser72Pro substitution in one allele, and a nonsense mutation Trp168X in the other. Ser72 is not a catalytic residue, but is required for the stabilization of the active site conformation. Thus, Ser72Pro exchange impairs the autocatalytic activation of the AGA precursor, and results in a considerable reduction of the enzyme activity and in altered AGA precursor processing. Betaine, which can partially rescue the AGA activity in AGU patients carrying certain missense mutations, turned out to be ineffective in the case of Ser72Pro substitution. The Trp168X nonsense allele results in complete lack of AGA polypeptide due to nonsense-mediated decay (NMD) of the mRNA. Amlexanox, which inhibits NMD and causes a translational read-through, facilitated the synthesis of a full-length, functional AGA protein from the nonsense allele. This could be demonstrated as presence of the AGA polypeptide and increased enzyme activity upon Amlexanox treatment. Furthermore, in the Ser72Pro/Trp168X expressing cells, Amlexanox induced a synergistic increase in AGA activity and polypeptide processing due to enhanced processing of the Ser72Pro polypeptide. Our data show for the first time that Amlexanox might provide a valid therapy for AGU.
2016-11-23 | Identification of Small Molecule Compounds for Pharmacological Chaperone Therapy of Aspartylglucosaminuria
Aspartylglucosaminuria (AGU) is a lysosomal storage disorder that is caused by genetic deficiency of the enzyme aspartylglucosaminidase (AGA) which is involved in glycoprotein degradation. AGU is a progressive disorder that results in severe mental retardation in early adulthood. No curative therapy is currently available for AGU. We have here characterized the consequences of a novel AGU mutation that results in Thr122Lys exchange in AGA, and compared this mutant form to one carrying the worldwide most common AGU mutation, AGU-Fin. We show that T122K mutated AGA is expressed in normal amounts and localized in lysosomes, but exhibits low AGA activity due to impaired processing of the precursor molecule into subunits. Coexpression of T122K with wildtype AGA results in processing of the precursor into subunits, implicating that the mutation causes a local misfolding that prevents the precursor from becoming processed. Similar data were obtained for the AGU-Fin mutant polypeptide. We have here also identified small chemical compounds that function as chemical or pharmacological chaperones for the mutant AGA. Treatment of patient fibroblasts with these compounds results in increased AGA activity and processing, implicating that these substances may be suitable for chaperone mediated therapy for AGU.
2026-01-07 | Pharmacological chaperone treatment with Cystadane for aspartylglucosaminuria: an open-label, phase 1b/2, clinical trial
Aspartylglucosaminuria (AGU) is a lysosomal storage disorder caused by a deficiency of the enzyme aspartylglucosaminidase (AGA) that is involved in glycoprotein breakdown. In the absence of this enzyme, glycoasparagines accumulate in the tissues and body fluids of the patients. No treatments targeting the disease cause are currently available. Our earlier findings show that betaine (tri-methyl glycine) functions as a pharmacological chaperone for the mutated AGA enzyme, resulting in an increased AGA activity in patient cells with pathogenic AGA missense variants. Here, we have carried out a phase 1b/2, open label clinical study (EudraCT number 2017-000645-48) with a clinically approved betaine product, Cystadane, in 21 Finnish AGU patients aged between 7.5 and 15 years at study begin, and homozygous for a specific missense variant. Cystadane was orally administrated for 48 months using a dose escalation strategy with a 3-month treatment break after the first year. The results of our study show that betaine is safe and well tolerated in AGU, and use of betaine results in a significant reduction of glycoasparagines in the urine, the primary endpoint of the study, as well as in a concomitant increase in serum AGA activity (a secondary endpoint). Exploratory neuropsychological findings showed significant improvements in some domains of the Wechsler’s Intelligence Scale for Children IV. Magnetic resonance imaging demonstrated that iron accumulation in specific thalamic regions of the patients is reduced due to betaine treatment. Our positive results encourage larger clinical trials with betaine in AGU.
2022-01-13 | Towards Splicing Therapy for Lysosomal Storage Disorders: Methylxanthines and Luteolin Ameliorate Splicing Defects in Aspartylglucosaminuria and Classic Late Infantile Neuronal Ceroid Lipofuscinosis.
Splicing defects caused by mutations in the consensus sequences at the borders of introns and exons are common in human diseases. Such defects frequently result in a complete loss of function of the protein in question. Therapy approaches based on antisense oligonucleotides for specific gene mutations have been developed in the past, but they are very expensive and require invasive, life-long administration. Thus, modulation of splicing by means of small molecules is of great interest for the therapy of genetic diseases resulting from splice-site mutations. Using minigene approaches and patient cells, we here show that methylxanthine derivatives and the food-derived flavonoid luteolin are able to enhance the correct splicing of the AGA mRNA with a splice-site mutation c.128-2A>G in aspartylglucosaminuria, and result in increased AGA enzyme activity in patient cells. Furthermore, we also show that one of the most common disease causing TPP1 gene variants in classic late infantile neuronal ceroid lipofuscinosis may also be amenable to splicing modulation using similar substances. Therefore, our data suggest that splice-modulation with small molecules may be a valid therapy option for lysosomal storage disorders.
2019-04-09 | The T99K variant of glycosylasparaginase shows a new structural mechanism of the genetic disease aspartylglucosaminuria
Aspartylglucosaminuria (AGU) is an inherited disease caused by mutations in a lysosomal amidase called aspartylglucosaminidase (AGA) or glycosylasparaginase (GA). This disorder results in an accumulation of glycoasparagines in the lysosomes of virtually all cell types, with severe clinical symptoms affecting the central nervous system, skeletal abnormalities, and connective tissue lesions. GA is synthesized as a single-chain precursor that requires an intramolecular autoprocessing to form a mature amidase. Previously, we showed that a Canadian AGU mutation disrupts this obligatory intramolecular autoprocessing with the enzyme trapped as an inactive precursor. Here, we report biochemical and structural characterization of a model enzyme corresponding to a new American AGU allele, the T99K variant. Unlike other variants with known 3D structures, this T99K model enzyme still has autoprocessing capacity to generate a mature form. However, its amidase activity to digest glycoasparagines remains low, consistent with its association with AGU. We have determined a 1.5-Å-resolution structure of this new AGU model enzyme and built an enzyme-substrate complex to provide a structural basis to analyze the negative effects of the T99K point mutation on KM and kcat of the amidase. It appears that a "molecular clamp" capable of fixing local disorders at the dimer interface might be able to rescue the deficiency of this new AGU variant.
2018-03-01 | Amlexanox provides a potential therapy for nonsense mutations in the lysosomal storage disorder Aspartylglucosaminuria
Aspartylglucosaminuria (AGU) is a lysosomal storage disorder caused by mutations in the gene for aspartylglucosaminidase (AGA). This enzyme participates in glycoprotein degradation in lysosomes. AGU results in progressive mental retardation, and no curative therapy is currently available. We have here characterized the consequences of AGA gene mutations in a compound heterozygous patient who exhibits a missense mutation producing a Ser72Pro substitution in one allele, and a nonsense mutation Trp168X in the other. Ser72 is not a catalytic residue, but is required for the stabilization of the active site conformation. Thus, Ser72Pro exchange impairs the autocatalytic activation of the AGA precursor, and results in a considerable reduction of the enzyme activity and in altered AGA precursor processing. Betaine, which can partially rescue the AGA activity in AGU patients carrying certain missense mutations, turned out to be ineffective in the case of Ser72Pro substitution. The Trp168X nonsense allele results in complete lack of AGA polypeptide due to nonsense-mediated decay (NMD) of the mRNA. Amlexanox, which inhibits NMD and causes a translational read-through, facilitated the synthesis of a full-length, functional AGA protein from the nonsense allele. This could be demonstrated as presence of the AGA polypeptide and increased enzyme activity upon Amlexanox treatment. Furthermore, in the Ser72Pro/Trp168X expressing cells, Amlexanox induced a synergistic increase in AGA activity and polypeptide processing due to enhanced processing of the Ser72Pro polypeptide. Our data show for the first time that Amlexanox might provide a valid therapy for AGU.
2016-11-23 | Identification of Small Molecule Compounds for Pharmacological Chaperone Therapy of Aspartylglucosaminuria
Aspartylglucosaminuria (AGU) is a lysosomal storage disorder that is caused by genetic deficiency of the enzyme aspartylglucosaminidase (AGA) which is involved in glycoprotein degradation. AGU is a progressive disorder that results in severe mental retardation in early adulthood. No curative therapy is currently available for AGU. We have here characterized the consequences of a novel AGU mutation that results in Thr122Lys exchange in AGA, and compared this mutant form to one carrying the worldwide most common AGU mutation, AGU-Fin. We show that T122K mutated AGA is expressed in normal amounts and localized in lysosomes, but exhibits low AGA activity due to impaired processing of the precursor molecule into subunits. Coexpression of T122K with wildtype AGA results in processing of the precursor into subunits, implicating that the mutation causes a local misfolding that prevents the precursor from becoming processed. Similar data were obtained for the AGU-Fin mutant polypeptide. We have here also identified small chemical compounds that function as chemical or pharmacological chaperones for the mutant AGA. Treatment of patient fibroblasts with these compounds results in increased AGA activity and processing, implicating that these substances may be suitable for chaperone mediated therapy for AGU.
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Drug Discovery Landscape
3 orphan drug designations for Aspartylglucosaminuria.
3 orphan drug designations for Aspartylglucosaminuria.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
recombinant serotype 9 adeno-associated virus encoding a codon-optimized human aspartylglucosaminidase (AGA) transgene | gene therapies | FDA | 2024-11-26 | — | Rare Trait Hope Fund |
Adeno-associated viral vector serotype 9 encoding a codon-optimised human aspartylglucosaminidase transgene | gene therapies | EMA | 2020-10-19 | — | Transcrip Ireland Limited |
RECOMBINANT HUMAN ASPARTYLGLUCOSAMINIDASE | proteins | EMA | 2015-01-15 | — | Chiesi Farmaceutici S.p.A. |
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